The present invention relates to certain benzimidazole derivatives and their use in medical therapy particularly for the treatment or prophylaxis of virus infections such as those caused by herpes viruses. The invention also relates to the preparation of the benzimidazole derivatives and pharmaceutical formulations containing them.
Of the DNA viruses, those of the herpes group are the source of the most common viral illnesses in man. The group includes herpes simplex virus types 1 and 2 (HSV), varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpes virus type 6 (HHV-6) and human herpes virus type 7 (HHV-7). HSV-1 and HSV-2 are some of the most common infectious agents of man. Most of these viruses are able to persist in the host""s neural cells; once infected, individuals are at risk of recurrent clinical manifestations of infection which can be both physically and psychologically distressing.
HSV infection is often characterized by extensive and debilitating lesions of the skin, mouth and/or genitals. Primary infections may be subclinical although tend to be more severe than infections in individuals previously exposed to the virus. Ocular infection by HSV can lead to keratitis or cataracts thereby endangering the host""s sight. Infection in the new-born, in immunocompromised patients or penetration of the infection into the central nervous system can prove fatal. VZV is a herpes virus which causes chickenpox and shingles. Chickenpox is the primary disease produced in a host without immunity, and in young children is usually a mild illness characterized by a vesicular rash and fever. Shingles or zoster is the recurrent form of the disease which occurs in adults who were previously infected with VZV. The clinical manifestations of shingles are characterized by neuralgia and a vesicular skin rash that is unilateral and dermatomal in distribution. Spread of inflammation may lead to paralysis or convulsions. Coma can occur if the meninges become affected. VZV is of serious concern in patients receiving immunosuppressive drugs for transplant purposes or for treatment of malignant neoplasia and is a serious complication of AIDS patients due to their impaired immune system.
In common with other herpes viruses, infection with CMV leads to a lifelong association of virus and host. Congenital HCMV disease is characterized by jaundice, hepatosplenomegaly, petechial rash and multiple organ dysfunction and is associated with long-term sequelae such as hearing loss and mental deficiency. Infection can result in retinitis leading to blindness or, in less severe forms, failure to thrive, and susceptibility to chest and ear infections. CMV infection in patients whose immune systems are immature or who are immunocompromised for example as a result of malignancy, treatment with immunosuppressive drugs following transplantation or infection with Human Immunodeficiency Virus, may give rise to retinitis, colitis, esophagistis, hepatitis, meningoencephalitis, pneumonitis, gastrointestinal disorders and neurological diseases. In addition, these CMV disease syndromes can affect patients who are not immunocompromised.
The main disease caused by EBV is acute or chronic infectious mononucleosis (glandular fever). Examples of other EBV or EBV associated diseases include lymphoproliferative disease which frequently occurs in persons with congenital or acquired cellular immune deficiency, X-linked lymphoproliferative disease which occurs namely in young boys, EBV-associated B-cell tumors, Hodgkin""s disease, nasopharyngeal carcinoma, Burkitt lymphoma, non-Hodgkin B-cell lymphoma, thymomas and oral hairy leukoplakia. EBV infections have also been found in association with a variety of epithelial-cell-derived tumors of the upper and lower respiratory tracts including the lung.
HHV-6 has been shown to be a causative agent of infantum subitum in children and of kidney rejection and interstitial pneumonia in kidney and bone marrow transplant patients, respectively, and may be associated with other diseases such as multiple sclerosis. There is also evidence of repression of stem cell counts in bone marrow transplant patients. HHV-7 is of undetermined disease etiology.
Hepatitis B virus (HBV) is a viral pathogen of world-wide major importance. The virus is etiologically associated with primary hepatocellular carcinoma and is thought to cause 80% of the world""s liver cancer. Clinical effects of infection with HBV range from headache, fever, malaise, nausea, vomiting, anorexia and abdominal pains. Replication of the virus is usually controlled by the immune response, with a course of recovery lasting weeks or months in humans, but infection may be more severe leading to persistent chronic liver disease outlined above.
WO 92/07867 describes certain polysubstituted benzimidazole derivatives and their activity against HSV and CMV. U.S. Pat. Nos. 5,399,580 and 5,534,535 disclose antiviral nucleoside analogues containing a substituted benzimidazole base attached to a carbocyclic ring in place of the conventional sugar residue. U.S. Pat. No. 5,360,795 describes 2,5,6,-trichloro-1-(xcex2-D-5-deoxyribofuranosyl)benzimidazole and 2-bromo-5,6-dichloro-1-(xcex2-D 5-deoxyribofuranosyl)benzimidazole and their activity against HSV and CMV.
It has now been discovered that certain 5xe2x80x2-deoxy polysubstituted benzimidazole analogues are useful for the treatment or prophylaxis of viral infections.
According to a first aspect of the invention there is provided compounds of formula (I): 
wherein:
R1 is hydroxy; O-acetyl; or a halo atom;
R2 is hydroxy; O-acetyl; or a halo atom;
R3is hydrogen; a halo atom; azido; C2-6alkenyl; C2-6alkynyl; C6-14aryl C2-6alkenyl; C6-14arylC2-6alkynyl xe2x80x94NR8R9 (where R8 and R9 may be the same or different and are hydrogen, C1-8alkyl, cyanoC1-8alkyl, hydroxyC1-8alkyl, haloC1-8alkyl, C3-7cycloalkyl, C1-8alkylC3-7cycloalkyl, C2-6alkenyl, C3-7cycloalkylC1-8alkyl, C2-6alkynyl, C6-14aryl, C6-14arylC1-8alkyl, heterocycleC1-8alkyl, C1-8alkylcarbonyl, C6-14arylsulfonyl, C1-8alkysulfonyl, or R8R9 together with the N atom to which they are attached form a 3,4,5 or 6 membered heterocyclic ring); xe2x80x94OR10 (where R10 is hydrogen, C1-8alkyl, C6-14aryl, or C6-14arylC1-8alkyl, C2-6alkenyl, C2-6alkynyl, C6-14aryl C2-6alkenyl or C6-14arylC2-6alkynyl); or xe2x80x94SR11 (where R11 is hydrogen, C1-8alkyl, C6-14aryl, or C6-14arylC1-8alkyl);
R4, R5, R6, and R7 , which may be the same or different, are each independently selected from hydrogen; a halo atom; cyano; nitro; C6-14aryl; C6-14arylC1-8alkyl; xe2x80x94NR8R9 (where R8 and R9 may be the same or different and are hydrogen, C1-8alkyl, cyanoC1-8alkyl, hydroxyC1-8alkyl, haloC1-8alkyl, C3-7cycloalkyl, C1-8alkylC3-7cycloalkyl, C2-6alkenyl, C3-7cycloalkylC1-8alkyl, C2-6alkynyl, C6-14aryl, C6-14arylC1-8alkyl, heterocycleC1-8alkyl, C1-8alkylcarbonyl, xe2x80x94C6-14arylsulfonyl, C1-8alkysulfonyl, or R8R9 together with the N atom to which they are attached form a 3,4,5 or 6 membered heterocyclic ring); xe2x80x94OR10 (where R10 is hydrogen, C1-8alkyl, C6-14aryl, C6-14arylC1-8alkyl, C2-6alkenyl, C2-6alkynyl, C6-14aryl C2-6alkenyl or C6-14arylC2-6alkynyl); xe2x80x94SR12 (where R12 is hydrogen, C1-8alkyl, C6-14aryl, or C6-14arylC1-8alkyl); trifluoromethyl; xe2x80x94S(O)2R13 (where R13 is hydrogen, C1-8alkyl, C6-14aryl, or C6-14arylC1-8alkyl); C(O)NR14R15 (where R14 and R15 may be the same or different and are hydrogen, C1-8alkyl, C6-14aryl, or C6-14arylC1-8alkyl); heterocycle or heterocycleC1-8alkyl;
provided that when R5 and R6 are Cl, R4 and R7 are hydrogen and R3 is Cl or Br; then R1 and R2 are not hydroxy or O-acetyl;
or a pharmaceutically acceptable derivative thereof.
Preferred compounds of formula (I) are the beta anomers of compounds of formula (I).
In a further aspect of the invention there is provided compounds of formula (Ia) 
wherein:
R1 is hydroxy or O-acetyl;
R2 is hydroxy, O-acetyl, or a fluorine atom;
R3 is a halo atom or xe2x80x94NR8R9 (wherein R8 and R9 are as hereinbefore defined).
R4 is hydrogen, a halo atom, nitrile, trifluoromethyl, or nitro;
R5 and R6 may be the same or different and are hydrogen, a halo atom, nitrile, trifluoromethyl, nitro, or xe2x80x94SR12 (wherein R12 is as hereinbefore defined);
R7 is hydrogen or a halo atom;
provided that when R5 and R6 are Cl, R4 and R7are hydrogen and R3 is Cl or Br; then R1 and R2 are not hydroxy or O-acetyl;
or a pharmaceutically acceptable derivative thereof.
Preferred compounds of formula (Ia) are the beta anomers of compounds of formula (Ia).
In a further aspect of the invention there is provided compounds of formula (Ib): 
wherein:
R1 is hydroxy or O-acetyl;
R2 is hydroxy, O-acetyl, or a fluorine atom;
R3 is a halo atom, or xe2x80x94NR8R9, wherein R8 is hydrogen and R9 is a C1-6 alkyl, or C3-7cycloalkyl;
R4 is hydrogen or a halo atom;
R5 and R6 may be the same or different and are hydrogen, a halo atom, nitro, nitrile, trifluoromethyl or xe2x80x94SR12 wherein R12 is C1-6alkyl;
R7 is hydrogen or fluorine;
provided that when R5 and R6 are Cl, R4 and R7 are hydrogen and R3 is Cl or Br; then R1 and R2 are not hydroxy or O-acetyl;
or a pharmaceutically acceptable derivative thereof.
Preferred compounds of formula (Ib) are the beta anomers of compounds of formula (Ib).
In a further aspect of the invention, there is provided compounds of formula (Ic) 
wherein:
R1 is hydroxy;
R2 is hydroxy, or a fluorine atom;
R3 is a halo atom, or xe2x80x94NR8R9, wherein R8 is hydrogen and R9 is a C1-6 alkyl, or C3-7cycloalkyl;
R4 is hydrogen or a halo atom;
R5 and R6 may be the same or different and are hydrogen, a halo atom, nitro, nitrite, trifluoromethyl, CH3, or xe2x80x94SR12 wherein R12 is C1-6alkyl;
R7 is hydrogen or fluorine;
provided that when R5 and R6 are Cl, R4 and R7 are hydrogen and R3 is Cl or Br, then R1 and R2 are not hydroxy or O-acetyl;
or a pharmaceutically acceptable derivative thereof.
Preferred compounds of formula (Ic) are the beta anomers of compounds of formula (Ic).
In a further aspect of the invention there is provided compounds of formula (Id): 
R1 is hydroxy;
R2 is hydroxy, or a fluorine atom;
R3 is a halo atom, or xe2x80x94NR8R9, wherein R8 is hydrogen and R9 is a C1-6 alkyl, or C3-7cycloalkyl;
R4 is hydrogen or a halo atom;
R5 and R6 may be the same or different and are hydrogen, a halo atom, nitro, nitrile, trifluoromethyl, CH3, or xe2x80x94SR12 wherein R12 is C1-6alkyl;
R7 is hydrogen or fluorine;
provided that R1 and R2 are cis to each other; and further provided that when R5 and R6 are Cl, R4 and R7 are hydrogen and R3 is Cl or Br; then R1 and R2 are not hydroxy or O-acetyl;
or a pharmaceutically acceptable derivative thereof.
Preferred compounds of formula (Id) are the beta anomers of compounds of formula (Id).
In a further aspect of the present invention there is provided compounds of formula (Ie) 
wherein:
R1 is hydroxy; O-acetyl; or a halo atom;
R2 is hydroxy; O-acetyl; or a halo atom;
R3 is hydrogen; a halo atom; azido; C2-6alkenyl; C2-6alkynyl; aryl C2-6alkenyl; C6-14aryl C2-6alkynyl; xe2x80x94NR8R9 (where R8 and R9 may be the same or different and are hydrogen, C1-8alkyl, cyanoC1-8alkyl, hydroxyC1-8alkyl, haloC1-8alkyl, C3-7cycloalkyl, C1-8alkylC3-7cycloalkyl, C2-6alkenyl, C3-7cycloalkylC1-8alkyl, C2-6alkynyl, C6-14aryl, C6-14arylC1-8alkyl, heterocycleC, 8alkyl, C1-8alkylcarbonyl, C6-14arylsulfonyl, C1-8alkysulfonyl, or R8R9 together with the N atom to which they are attached form a 3,4,5 or 6 membered heterocyclic ring); xe2x80x94OR10 (where R10 is hydrogen, C1-8alkyl, C6-14aryl, or C6-14arylC1-8alkyl, C2-6alkenyl, C2-6alkynyl, C6-14aryl C2-6alkenyl or C6-14aryl C2-6alkynyl); or xe2x80x94SR11 (where R11 is hydrogen, C1-8alkyl, C6-14aryl, or C6-14arylC1-8alkyl);
R4, R5, R6, and R7 , which may be the same or different, are each independently selected from hydrogen; a halo atom; cyano; nitro; C6-14aryl; C6-14arylC1-8alkyl; xe2x80x94NR8R9 (where R8 and R9 may be the same or different and are hydrogen, C1-8alkyl, cyanoC1-8alkyl, hydroxyC1-8alkyl, haloC1-8alkyl, C3-7cycloalkyl, C1-8alkylC3-7cycloalkyl, C2-6alkenyl, C3-7cycloalkylC1-8alkyl, C2-6alkynyl, C6-14aryl, C6-14arylC1-8alkyl, heterocycleC1-8alkyl, C1-8alkylcarbonyl, C6-14arylsulfonyl, C1-8alkysulfonyl, or R8R9 together with the N atom to which they are attached form a 3,4,5 or 6 membered heterocyclic ring); xe2x80x94OR10 (where R10 is hydrogen, C1-8alkyl, C6-14aryl, C6-14arylC1-8alkyl, C2-6alkenyl, C2-6alkynyl, C6-14aryl C2-6alkenyl or C6-14arylC2-6alkynyl); xe2x80x94SR12 (where R12 is hydrogen, C1-8alkyl, C6-14aryl, or C6-14arylC1-8alkyl); trifluoromethyl; xe2x80x94S(O)2R13 (where R13 is hydrogen, C1-8alkyl, C6-14aryl, or C6-14arylC1-8alkyl); C(O)NR14R15 (where R14 and R15 may be the same or different and are hydrogen, C1-8alkyl, C6-14aryl, or C6-14arylC1-8alkyl); heterocycle; or heterocycle C1-8alkyl.
provided that when R5 and R6 are Cl, R4 and R7 are H and R3 is Cl or Br; then R1 and R2 are not hydroxy or O-acetyl;
or a pharmaceutically acceptable derivative thereof.
The compounds of formula (I) including compounds of formula (Ia), (Ib), and (Ic), (Id), and Ie) above and their pharmaceutically acceptable derivatives are hereinafter referred to as the compounds according to the invention.
The compounds according to the invention contain one or more asymmetric carbon atoms and thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers, and regioisomers. All such isomeric forms of these compounds are expressly included in the present invention. Each stereogenic carbon may be of the R or S configuration. Although the specific compounds exemplified in this application may be depicted in a particular stereochemical configuration, compounds having either the opposite stereochemistry at any given chiral center or mixtures thereof are also envisioned.
The present invention includes within its scope each possible alpha and beta anomer of the compounds of formula (I) and their physiologically functional derivatives, substantially free of the other anomer, that is to say no more than about 5% w/w of the other anomer. Compounds of formula (I) in the beta ribofuranosyl anomeric form are preferred.
Preferred compounds according to the invention include:
5,6-Dichloro-1-(5-deoxy-beta-D-ribofuranosyl)-N-(cyclopropyl)-1H-benzimidazol-2-amine;
5,6-Dichloro-1-(5-deoxy-beta-D-ribofuranosyl)-N-(1 -methylethyl)-1H-benzimidazol-2-amine;
2-Azetidino-5,6-dichloro-1-(5-deoxy-beta-D-ribofuranosyl)1H-benzimidazole;
5,6-Dichloro-1-(5-deoxy-beta-D-ribofuranosyl)-N-(cyclopentyl)-1H-benzimidazol-2-amine;
5,6-Dichloro-1-(5-deoxy-beta-D-ribofuranosyl)-O-(isopropyl)-1H-benzimidazol-2-one;
5,6-Dichloro-1-(5-deoxy-beta-D-ribofuranosyl)-N-(n-hexyl)-1H-benzimidazol-2-amine;
5,6-Dichloro-1-(5-deoxy-beta-D-ribofuranosyl)-N-((R)-sec-butyl)-1H-benzimidazol-2-amine;
5,6-Dichloro-1-(5-deoxy-beta-D-ribofuranosyl)-N-((S)-sec-butyl)-1H-benzimidazol-2-amine;
6-Trifluoromethyl-1-(5-deoxy-beta-D-ribofuranosyl)-N-(1-methylethyl)-1H-benzimidazol-2-amine;
2-Bromo-6-trifluoromethyl-1-(5-deoxy-beta-D-ribofuranosyl)-1H-benzimidazole;
5-Nitro-1-(5-deoxy-beta-D-ribofuranosyl)-N-(1-methylethyl)-1H-benzimidazol-2-amine;
6-Nitro-1-(5-deoxy-beta-D-ribofuranosyl)-N-(1-methylethyl)-1H-benzimidazol-2-amine;
5-Chloro-6-trifluoromethyl-1-(5-deoxy-beta-D-ribofuranosyl)-N-(1-methylethyl)-1H-benzimidazol-2-amine;
6-Chloro-5-trifluoromethyl-1-(5-deoxy-beta-D-ribofuranosyl)-N-(1-methylethyl)-1H-benzimidazol-2-amine;
2-Bromo-6-chloro-1-(5-deoxy-beta-D-ribofuranosyl)-1H-benzimidazole;
2-Bromo-5-chloro-1-(5-deoxy-beta-D-ribofuranosyl)-1H-benzimidazole;
6-Chloro-4,5-difluoro-1-(5-deoxy-beta-D-ribofuranosyl)-N-(1-methylethyl)-1H-benzimidazol-2-amine;
4,5,6-Trifluoro-1-(5-deoxy-beta-D-ribofuranosyl)-N-(1-methylethyl)1H-benzimidazol-2-amine;
5-Chloro-6-methylthio-1-(5-deoxy-beta-D-ribofuranosyl)-N-(1-methylethyl)-1H-benzimidazol-2-amine;
5,6,-Dichloro-4-fluoro-1-(5-deoxy-beta-D-ribofuranosyl)-N-(1-methylethyl)-1H-benzimidazol-2-amine;
5,6-Dichloro-7-fluoro-1-(5-deoxy-beta-D-ribofuranosyl)-N-(1-methylethyl)-1H-benzimidazol-2-amine; and
2,5,6-Trichloro-1-(5deoxy-xcex1-D-lyxofuranosyl)benzimidazole.
The term xe2x80x9chydroxyxe2x80x9d, alone or in combination with any other term, refers to monohydroxylated or polyhydroxylated substituents.
The term xe2x80x9calkylxe2x80x9d, alone or in combination with any other term, refers to a straight-chain or branch-chain saturated aliphatic hydrocarbon radical containing the specified number of carbon atoms, or where no number is specified, preferably from 1-10 and more preferably from 1-6 carbon atoms, optionally substituted with one or more substituents selected from C1-6 alkoxy, (for example methoxy), nitro, halogen, (for example chloro), amino, carboxylate and hydroxy. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, n-hexyl and the like.
The term xe2x80x9calkenyl, xe2x80x9d alone or in combination with any other term, refers to a straight-chain or branched-chain mono- or poly-unsaturated aliphatic hydrocarbon radical containing the specified number of carbon atoms, or where no number is specified, preferably from 2-10 carbon atoms and more preferably, from 2-6 carbon atoms. References to alkenyl groups include groups which may be in the E- or Z-form or a mixture thereof and which when they contain at least three carbon atoms, may be branched. Examples of alkenyl radicals include, but are not limited to, ethenyl, E- and Z-propenyl, isopropenyl, E- and Z-butenyl, E- and Z-isobutyenyl, E- and Z-pentenyl, E- and Z-hexenyl, E,E-, E,Z-, Z, E- and Z,Z-hexadienyl and the like.
The term xe2x80x9calkynylxe2x80x9d refers to hydrocarbon groups of either a straight or branched configuration with one or more carbon-carbon triple bonds which may occur in any stable point along the chain, such as ethynyl, propynyl, butynyl, pentynyl, and the like.
The term xe2x80x9calkoxyxe2x80x9d refers to an alkyl ether radical, wherein the term xe2x80x9calkylxe2x80x9d is defined above. Examples of suitable alkyl ether radicals include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
Alkenyl and alkynyl substituents may optionally contain one or more heteroatoms such as nitrogen, sulfur, or oxygen.
The term xe2x80x9caryl, xe2x80x9d alone or in combination with any other term, refers to a carbocyclic aromatic radical (such as phenyl or naphthyl) containing the specified number of carbon atoms, preferably from 6-14 carbon atoms, and more preferably from 6-10 carbon atoms, optionally substituted with one or more substituents selected from C1-6 alkoxy, (for example methoxy), nitro, halogen, (for example chloro), amino, carboxylate and hydroxy. Examples of aryl radicals include, but are not limited to phenyl, naphthyl, indenyl, indanyl, azulenyl, fluorenyl, anthracenyl and the like.
The term xe2x80x9cheterocyclexe2x80x9d and xe2x80x9cheterocyclylxe2x80x9d radical, unless otherwise defined herein, refers to a stable 3-7 membered monocyclic heterocyclcic ring or 8-11 membered bicyclic heterocycicic ring which is either saturated or unsaturated, and which may be optionally benzofused if monocyclic. Each heterocycle consists of one or more carbon atoms and from one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. As used herein, the terms xe2x80x9cnitrogen and sulfur heteroatomsxe2x80x9d include any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen. A heterocyclyl radical may be attached at any endocyclic carbon or heteroatom which results in the creation of a stable structure. Preferred heterocycles include 5-7 membered monocyclic heterocycles and 8-10 membered bicyclic heterocycles. Examples of such groups include imidazolyl, imidazolinoyl, imidazolidinyl, quinolyl, isoqinolyl, indolyl, indazolyl, indazolinolyl, perhydropyridazyl, pyridazyl, pyridyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazinyl, quinoxolyl, piperidinyl, pyranyl, pyrazolinyl, piperazinyl, pyrimidinyl, pyridazinyl, morpholinyl, thiamorpholinyl, furyl, thienyl, triazolyl, thiazolyl, carbolinyl, tetrazolyl, thiazolidinyl, benzofuranoyl, thiamorpholinyl sulfone, oxazolyl, benzoxazolyl, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, azepinyl, isoxozolyl, isothiazolyl, furazanyl, tetrahydropyranyl, tetrahydrofuranyl, thiazolyl, thiadiazoyl, dioxolyl, dioxinyl, oxathiolyl, benzodioxolyl, dithiolyl, thiophenyl, tetrahydrothiophenyl, sulfolanyl, dioxanyl, dioxolanyl, tetahydrofurodihydrofuranyl, tetrahydropyuranodihydrofuranyl, dihydropyranyl, tetradyrofurofuranyl and tetrahydropyranofuranyl.
Preferred heterocycles include imidazolyl, pyrrolyl, pyrrolinyl, piperidinyl, piperazinyl, and morpholinyl.
The term xe2x80x9chalo atomxe2x80x9d or xe2x80x9chalogenxe2x80x9d refers to a radical of fluorine, chlorine, bromine or iodine.
The term xe2x80x9chaloC1-6alkylxe2x80x9d means an alkyl group in which one or more hydrogens is replaced by halo and preferably containing one, two or three halo groups. Examples of such groups include trifluoromethyl and fluoroisopropyl.
The term xe2x80x9cpharmaceutically effective amountxe2x80x9d refers to an amount effective in treating a viral infection in a patient either as monotherapy or in combination with other agents. The term xe2x80x9ctreatingxe2x80x9d as used herein refers to the alleviation of symptoms of a particular disorder in a patient or the improvement of an ascertainable measurement associated with a particular disorder. The term xe2x80x9cprophylactically effective amountxe2x80x9d refers to an amount effective in preventing viral infection in a patient. As used herein, the term xe2x80x9cpatientxe2x80x9d refers to a mammal, including a human.
The term xe2x80x9cpharmaceutically acceptable carrier or adjuvantxe2x80x9d refers to a carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered indoses sufficient to deliver a therapeutic amount of the antiviral agent.
As used herein, the compounds according to the invention are defined to include pharmaceutically acceptable derivatives or prodrugs thereof. A xe2x80x9cpharmaceutically acceptable derivativexe2x80x9d or xe2x80x9cpharmaceutically acceptable prodrugxe2x80x9d means any pharmaceutically acceptable salt, ester, salt of an ester, solvate, such as ethanolate, or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention or an inhibitorily active metabolite or residue thereof. Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.
The compounds according to the invention may be used in the form of salts derived from inorganic or organic acids. Included among such acid salts, for example, are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectianate, persulfate, phenylproprionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.
Pharmaceutically acceptable salts of the compounds according to the invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicyclic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
Salts derived from appropriate bases include alkali metal (e.g. sodium), alkaline earth metal (e.g., magnesium), ammonium and Nxe2x88x92W+4 (wherein W is C1-4 alkyl). Physiologically acceptable salts of a hydrogen atom or an amino group include salts or organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids. Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as Na+, NH4+, and NW4+(wherein W is a C1-4alkyl group).
Pharmaceutically acceptable salts include salts of organic carboxylic acids such as ascorbic, acetic, citric, lactic, tartaric, malic, maleic, isothionic, lactobionic, p-aminobenzoic and succinic acids; organic sulphonic acids such as methanesulphonic, ethanesulphonic, benzenesulphonic and p-toluenesulphonic acids and inorganic acids such as hydrochloric, sulphuric, phosphoric, sulphamic and pyrophosphoric acids.
For therapeutic use, salts of the compounds of formula (I) will be pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
Preferred salts include salts formed from hydrochloric, sulfuric, acetic, succinic, citric and ascorbic acids.
Preferred esters of the compounds according to the invention are independently selected from the following groups: (1) carboxylic acid esters obtained by esterification of the 2xe2x80x2-, 3xe2x80x2- and/or 5xe2x80x2-dehydroxy groups, in which the nonarbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted by, for example, halogen, C1-4alkyl, or C1-4alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a C1-20 alcohol or reactive derivative thereof, or by a 2,3-di (C6-24)acyl glycerol.
In such esters, unless otherwise specified, any alkyl moiety present advantageously contains from 1 to 18 carbon atoms, particularly from 1 to 6 carbon atoms, more particularly from 1 to 4 carbon atoms, Any cycloalkyl moiety present in such esters advantageously contains from 3 to 6 carbon atoms. Any aryl moiety present in such esters advantageously comprises a phenyl group.
Any reference to any of the above compounds also includes a reference to pharmaceutically acceptable salts thereof.
Ethers of the compounds according to the invention include methyl, ethyl, propyl, butyl, isobutyl, and sec-butyl ethers.
In a further aspect of the invention there are provided the compounds according to the invention for use in medical therapy particularly for the treatment or preophylaxis of viral infections such as herpes viral infections. Compounds of the invention have been shown to be active against CMV infections, although early results suggest that these compounds could also be active against other herpes virus infections such as HSV-1 and-2, HHV 6 and 7, VZV, EBV and HBV infections.
Other viral conditions which may be treated in accordance with the invention have been discussed in the introduction hereinbefore. The compounds of the present invention are particularly suited to the treatment or prophylaxis of CMV infections and associated conditions. Examples of CMV conditions which may be treated in accordance with the invention have been discussed in the introduction hereinbefore.
According to another aspect, the present invention provides a method for the treatment or prevention of the symptoms or effects of a viral infection in an infected animal, for example, a mammal including a human, which comprises treating said animal with a therapeutically effective amount of a compound according to the invention. According to a particular embodiment of this aspect of the invention, the viral infection is a herpes virus infection, such as CMV, HSV-1, HSV-2, VZV, EBV, HHV6 or HHV7. A further aspect of the invention includes a method for the treatment or prevention of the symptoms or effects of an HBV infection.
The present invention further provides a method for the treatment of a clinical condition in an animal, for example, a mammal including a human which clinical condition includes those which have been discussed in the introduction hereinbefore, which comprises treating said animal with a therapeutically effective amount of a compound according to the invention. The present invention also includes a method for the treatment or prophylaxis of any of the aforementioned infections or conditions.
In yet a further aspect, the present invention provides the use of a compound according to the invention in the manufacture of a medicament for the treatment or prophylaxis of any of the above mentioned viral infections or conditions.
The above compounds according to the invention and their pharmaceutically acceptable derivatives may be employed in combination with other therapeutic agents for the treatment of the above infections or conditions. Combination therapies according to the present invention comprise the administration of at least one compound of the formula (I) or a pharmaceutically acceptable derivative thereof and at least one other pharmaceutically active ingredient. The active ingredient(s) and pharmaceutically active agents may be administered simultaneously in either the same or different pharmaceutical formulations or sequentially in any order. The amounts of the active ingredient(s) and pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect. Preferably the combination therapy involves the administration of one compound according to the invention and one of the agents mentioned herein below.
Examples of such further therapeutic agents include agents that are effective for the treatment of viral infections or associated conditions are (1 alpha, 2 beta, 3 alpha)-9-[2,3-bis(hydroxymethyl)cyclobutyl]guanine [(xe2x88x92)BHCG, SQ-34514], oxetanocin-G(3,4-bis(hydroxymethyl)-2-oxetanosyl]guanine), acyclic nucleosides (e.g. acyclovir, valaciclovir, famciclovir, ganciclovir, penciclovir), acyclic nucleoside phosphonates (e.g. (S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl)cytosine (HPMPC), ribonucleotide reductase inhibitors such as 2-acetylpyridine 5-[(2-chloroanilino)thiocarbonyl)thiocarbonohydra-zone, 3xe2x80x2azido-3xe2x80x2-deoxythymidine, other 2xe2x80x2,3xe2x80x2-dideoxynucleosides such as 2xe2x80x2,3xe2x80x2-dideoxycytidine, 2xe2x80x2,3xe2x80x2-dideoxyadenosine, 2xe2x80x2,3xe2x80x2-dideoxyinosine, 2xe2x80x2,3xe2x80x2-didehydrothymidine, protease inhibitors such as ritonovir, indinavir, 141W94, nelfinavir, sanquinavir, and 3S-[3R*(1S*,2R*)]-[3-[[(4-aminophenyl)sulphonyl](2-methylpropyl)-amino]-2-hydroxy-1-phenylmethyl)propyl]carbamic acid, tetrahydro-3-furanyl ester (141W94), oxathiolane nucleoside analogues such as (xe2x88x92)-cis-1-(2-hydroxymethyl)-1,3-oxathiolane 5-yl)-cytosine (lamivudine) or cis-1-(2-(hydroxymethyly1,3-oxathiolan-5-yl)-5-fluorocytosine (FTC), 3xe2x80x2-deoxy-3xe2x80x2-fluorothymidine, 5-chloro-2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluorouridine, (xe2x88x92)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol, ribavirin, 9-[4-hydroxy-2-(hydroxymethyl)but-1-yl]-guanine (H2G), tat inhibitors such as 7-chloro-5-(2-pyrryl)-3H-1,4-benzodiazepin-2-(H)one (Ro5-3335), 7-chloro-1,3-dihydro-5-(1H-pyrrol-2yl)-3H-1,4-benzodiazepin-2-amine (Ro24-7429), interferons such as xcex1-interferon, renal excretion inhibitors such as probenecid, nucleoside transport inhibitors such as dipyridamole; pentoxifylline, N-acetylcysteine (NAC), Procysteine, xcex1-trichosanthin, phosphonoformic acid, as well as immunomodulators such as interleukin II or thymosin, granulocyte macrophage colony stimulating factors, erythropoetin, soluble CD4 and genetically engineered derivatives thereof, or non-nucleoside reverse transcriptase inhibitors such as nevirapine (BI-RG-587), loviride (xcex1-APA) and delavuridine (BHAP), and phosphonoformic acid.
More preferably the combination therapy involves the administration of one of the above mentioned agents and a compound within one of the preferred or particularly preferred sub-groups within formula (I) as described above. Most preferably the combination therapy involves the joint use of one of the above named agents together with one of the compounds of formula (I) specifically named herein.
The present invention further includes the use of a compound according to the invention in the manufacture of a medicament for simultaneous or sequential administration with at least one other therapeutic agent, such as those defined hereinbefore.
In a further aspect of the present invention there is provided a method of treatment or prophylaxis of restenosis by administration of a compound according to the invention.
Restensosis is the narrowing of the blood vessels which can occur after injury to the vessel wall, for example injury caused by balloon angioplasty or other surgical techniques, and is characterized by excessive proliferation of smooth muscle cells in the walls of the blood vessel treated. Restenosis following angioplasty (RFA) occurs in patients who have been treated for coronary artery disease by balloon angioplasty. It is thought that in many patients suffering from RFA, viral infection, particularly by CMV and/or HHV-6, of the patient plays a pivotal role in the proliferation of the smooth muscle cells in the coronary vessel treated.
Restenosis can occur following a number of surgical techniques, for example, transplant surgery, vein grafting, coronary by-pass grafting and, most commonly, following angioplasty.
Angioplasty is a surgical technique wherein atherosclerotic stenoses in the peripheral, renal and coronary vasculature are opened up by compressing and/or tearing the plaque on the vessel walls, typically by means of a pressurized balloon catheter. Unfortunately, in 25 to 50% of cases, particularly those involving the coronary vasculature, the treated vessel restenoses within a few months so that the operation must be repeated. Alternatives to the balloon catheter, such as pulsed lasers and rotary cutters, have been developed with a view to reducing or preventing restenosis following angioplasty, but have met with limited success. A number of drugs including anti-coagulants and vasodilators have also been tried with disappointing or equivocal results.
There is now a strong body of evidence, from work done both in vitro and in vivo, indicating that restenosis is a multifactorial process. Several cytokines and growth factors, acting in concert, stimulate the migration and proliferation of vascular smooth muscle cells (SMC) and production of extracellular matrix material, which accumulate to occlude the blood vessel. In addition growth suppressors act to inhibit the proliferation of SMC""s and production of extracellular matrix material.
The present invention further includes a process for the preparation of compounds of formula (I) and pharmaceutically acceptable derivatives thereof which comprises:
A. Reacting a compound of formula (I) wherein R3 is hydrogen and R4, R5, R6 and R7 are as hereinbefore defined, and R1 and R2 are a hydroxy group, protected hydroxy or a fluorine atom, with a suitable halogenation agent such as N-bromosuccinimide (NBS); or when R3 is a suitable leaving atom or group, for example, a halo atom such as bromine or an organo (for example alkyl) sulphone, or organo (for example alkyl or aralkyl) sulphonate such as methylsulphone (MeS(O)2xe2x80x94), methylsulphonate (MeS(O)2Oxe2x80x94) or tosylate (4-MePhS(O)2Oxe2x80x94) with an amine of the formula HNR8R9 (wherein R8 and R9 are as hereinbefore defined), an alcohol of formula HOR10 (where R10 is as hereinbefore defined), a thiol of the formula HSR11 (wherein R11 is as hereinbefore defined), or a suitable displacing agent such as tetrabutyl ammonium azide or sodium azide or potassium azide.
B. Reacting a compound of formula (II). 
wherein R3 is hydrogen, a halo atom, xe2x80x94NR8R9 (wherein R8 and R9 are as hereinbefore defined), and R4, R5, R6 and R7 are as hereinbefore described with a compound of formula (III) 
wherein R1 and R2 are as is hereinbefore defined and L1 is a suitable leaving group in the alpha or beta position, for example, a halo (for example, fluoro, chloro or bromo), an alkyl or arylthio (for example, phenylthio) or an aryl or aliphatic ester group such as benzoate or acetate; and thereafter or simultaneously therewith effecting one or more of the following further steps may be additionally performed in any desired or necessary order:
(i) removing any remaining protecting group(s);
(ii) converting a compound of formula (I) or a protected form thereof into a further compound of formula (I) or protected form thereof;
(iii) converting the compound of formula (I) or a protected form thereof into a pharmaceutically acceptable derivative of the compound of formula (I) or a protected form thereof;
(iv) converting a pharmaceutically acceptable derivative of the compound of formula (I) or a protected form thereof into the compound of formula (I) of a protected form thereof;
(v) converting a pharmaceutically acceptable derivative of the compound of formula (I) or a protected form thereof into another pharmaceutically acceptable derivative of the compound of formula (I) or a protected form thereof;
(vi) where necessary, separating the alpha and beta anomers of the compound of formula (I) or of a protected derivative thereof or of a pharmaceutically acceptable derivative of a compound of formula (I).
Process A may conveniently be used for the preparation of a compound of formula (I) wherein R3 is a halogen. Such compounds may conveniently be prepared by reacting a compound of formula (I) wherein R3 is hydrogen and R1, R2, R4, R5, R6 and R7 are as hereinbefore defined with a halogenating agent. Halogenation may be effected in a conventional manner, for example, bromination using a brominating agent such as N-bromosuccinimide (NBS) in an aprotic solvent such as tetrahydrofuran (THF) or preferably 1,4-dioxane heated to 60-150xc2x0 C., preferably, 100xc2x0 C.
Compounds of formula (I) wherein R3 is xe2x80x94NR8R9 (wherein R8 and R9 are as hereinbefore defined) may conveniently be prepared from compounds of formula (I) wherein R3 is a halo atom, such as bromo or chloro atom, by reaction with an appropriate amine HNR8R9, wherein R8 and R9 are as hereinbefore defined. Typically, the reaction is effected at an elevated temperature, 70-80xc2x0 C., in an organic solvent such as ethanol or dimethylsulfoxide. Amines of formula HNR8R9 are commercially available or are readily prepared by a person skilled in the art.
Compounds of formula (I) wherein R3 is xe2x80x94OR10 (wherein R10 is as hereinbefore defined) may conveniently be prepared from compounds of formula (I) wherein R3 is a halo atom, such as bromo or chloro atom, by reaction with an appropriate alcohol of formula HOR8 (wherein R8 is as hereinbefore defined). Typically, the reaction is effected at xe2x88x9220 to 100xc2x0 C., preferably at 25xc2x0 C., in HOR8 or dimethylsulfoxide as solvent and in the presence of a strong base such as sodium hydride. Alcohols of formula HOR8 are available commercially or may be readily prepared by a person skilled in the art.
Compounds of formula (I) wherein R3 is xe2x80x94SR11 (wherein R11 is as hereinbefore defined) may conveniently be prepared from compounds of formula (I) wherein R3 is a halo atom, such as bromo or chloro atom, by reaction with an appropriate thiol of formula HSR11 (wherein R11 is as hereinbefore defined). Typically, the reaction is effected at xe2x88x9220 to 100xc2x0 C., preferably at 25xc2x0 C., in N,N-dimethylformamide or dimethylsulfoxide as solvent and in the presence of a strong base such as sodium or potassium hydride. Thiols of formula HSR11 are available commercially or may be readily prepared by a person skilled in the art.
Compounds of formula (I) wherein R3 is azido may conveniently be prepared from compounds of formula (I) wherein R3 is a halo atom, such as bromo or chloro atom, by reaction with an appropriate displacing agent such as tetrabutyl ammonium azide or potassium or sodium azide. Typically, the reaction is effected at an elevated temperature from 75-150xc2x0 C., preferably at 100xc2x0 C., and in the presence of a polar, aprotic solvent such as dimethylsulfoxide, preferably N,N-dimethylformamide.
Compounds of formula (I) in which R3, R4, R5, R6 or R7 is an alkenyl group and R1 and R2 are as hereinbefore defined can be prepared from compounds of formula (I) wherein R3, R4, R5, R6 or R7 are a halo atom, preferably a bromo atom, by reaction with an alkenyl trialkyltin (IV) reagent, such as vinyl tributyltin. These reactions are typically effected in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium (0), palladium (II) acetate, or palladium (II) chloride bis(acetonitrile) also in the presence of a solvent such as N,N-dimethylformamide and at an elevated temperature, preferably 90xc2x0 C. The desired alkenyl trialkyltin (IV) reagent is available commercially or may be readily prepared by a person skilled in the art.
Compounds of formula (I) in which R3, R4, R5, R6 or R7 is an alkynyl group and R1 and R2 are as hereinbefore defined may be conveniently prepared from compounds of formula (I) wherein R3, R4, R5, R6 or R7 is a halo atom, preferably a bromo atom, by reaction with a terminal acetylene, such as trimethylsilylacetylene. Typically, the reaction is effected in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium (0), palladium (II) acetate, or palladium (II) chloride bis(acetonitrile) and in the presence of copper (I) iodide. The reaction is also performed in the presence of a solvent, preferably N,N-dimethylformamide and a base, preferably triethylamine and at an elevated temperature from 40-100xc2x0 C., preferably 80xc2x0 C. The desired terminal acetylene may be obtained commerically or may be readily prepared by a person skilled in the art.
Compounds of formula (I) in which R4, R5, R6 or R7 is an aryl or heterocyclic group, and R1 and R2 are as hereinbefore defined, may be prepared from compounds of formula (I) in which R4, R5, R6 or R7 is a halo atom, such as a bromo atom, by reaction with an aryl or heterocyclic trialkyltin (IV) reagent. These reactions are typically effected in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium (0), palladium (II) acetate, or palladium (II) chloride bis(acetonitrile) also in the presence of a solvent such as N,N-dimethylformamide and at an elevated temperature, preferably 90xc2x0 C. The desired aryl or heterocyclic trialkyltin (IV) reagent may be obtained commercially or may be readily prepared by a person skilled in the art.
Alternatively, compounds of formula (I) in which R4, R5, R6 or R7 is a heterocyclic group, and R1 and R2 are as hereinbefore defined, may be prepared from compounds of formula (I) in which R4, R5, R6 or R7 is a nitrile radical by reaction with an agent capable of cyclizing the nitrile into a heterocycle. An example of such an agent is sodium azide, which upon reaction with a nitrile radical produces a tetrazolyl group. This reaction is typically effected in the presence of tributyltin (IV) chloride and in an aromatic solvent, toluene for example, and in the temperature range from 75-200xc2x0 C., preferably 110xc2x0 C.
Compounds of formula (I) in which R4, R5, R6 or R7 is xe2x80x94C(O)NR14R15, wherein R14 and R15 are as hereinbefore defined, may be prepared from compounds of formula (I) in which R4, R5, R6 or R7 is a nitrile radical by reaction with acid and water. This reaction is typically effected in a polar solvent, such as water, and in the presence of hydrogen peroxide at 25-100xc2x0 C., preferably 35xc2x0 C. Additionally, the reaction can be effected in the presence of an alkyl halide when R14 an alkyl group and R15 is either hydrogen or an alkyl group.
The protecting groups may be removed by conventional chemical techniques well known to a skilled person.
Compounds of formula (I) wherein R1 is a hydroxy group, R2 is either a hydroxy group or a fluorine atom and R3, R4, R5, R6 and R7 are as hereinbefore defined may be prepared from a corresponding compound of formula (I) wherein R1 is a protected hydroxy group and R2 is a protected hydroxy group or a fluorine atom. Conventional protecting groups may be used for R1 and R2. Advantageously, ester groups such as those described above in relation to the esters of compounds of formula (I) may be used. These protecting groups may be removed either by conventional chemical techniques such as sodium carbonate in water and methanol or enzymatically, for example, using pig liver esterase. Alternatively, R1 and R2 may include silyl ethers such as tert-butyldiphenyl-, tert-butyldimethyl-, and triisopropylsilyl ethers which may be deprotected to give a hydroxyl group using an appropriate fluoride source, for example HF/pyridine, Bu4NF or Et4NF or a cyclic acetal or ketal such as benzylidene or isopropylidene which can be removed under acidic conditions, for example, using tosic acid and methanol.
Alternatively, the compounds of formula (I) where R1 is a protected hydroxy group and R2 is either a protected hydroxy group or a fluorine atom and R4, R5, R6 and R7 are as hereinbefore defined may be reacted with an agent or under conditions whereby the leaving group R3 is converted to the desired R3 group simultaneously with removal of the protecting groups. Examples of such agents include cyclopropylamine and other primary and secondary amines providing that these agents are sufficiently nucleophilic and are not sterically hindered.
B. Compounds of formula (I) wherein R3 is as hereinbefore defined may be prepared by reaction of a compound of formula (II) wherein R3 is hydrogen, a halo atom or xe2x80x94NR8R9 (wherein R8 and R9 are as hereinbefore defined) and R4, R5, R6 and R7 are as hereinbefore defined, with a compound of formula (III), wherein R1 and R2 are each a hydroxy or protected hydroxy group and L1 is as hereinbefore described. The reaction of compounds of formula (II) with those of formula (III) may be effected using a Lewis acid such as trimethylsilyl trifluoromethanesulfonate, stannic chloride, or boron trifluoride, the former being preferred. The reaction is generally effected in an aprotic solvent and at an elevated temperature, for example, in acetonitrile at 15-30xc2x0 C. or 1,2-dichloroethane at 70-90xc2x0 C.
The compound of formula (II) is advantageously trimethylsilylated at the N1-position in the above procedures to improve solubility; for example, by treatment with trimethylsilylchloride, hexamethyl disilazane or, most preferably, N,O-bis(trimethylsilyl)acetamide (BSA). The silylation can be effected in a solvent, preferably 1,2-dichloroethane or acetonitrile, preferably at 70-80xc2x0 C. After completion of the silylation reaction, a Lewis acid may be added, followed by the addition of the compound of formula (III).
Compounds of formula (I), of the beta-D-ribofuranosyl configuration, wherein R1, R4, R5, R6, and R7 are as hereinbefore defined, R2 is fluoro and R3 is hydrogen may be prepared enzymatically by reacting a compound of formula (II) where R3 is hydrogen and R4, R5, R6 and R7 are as hereinbefore defined with a suitable carbohydrate donor such as a compound of formula (IV): 
where R16 is hydrogen. Enzymatic synthesis can be accomplished by N-deoxyribosyl transferase. The latter enzyme can be isolated by the procedure outlined by Cook, et. al., J. Biol. Chem. 1990, 265, 2682.
Compounds of formula (IV) where R16 hydrogen may be prepared from compounds of formula (IV) where R16 is a halo atom such as iodo with a suitable reducing agent such as tributyltin hydride or palladium on carbon in the presence of a base such as ammonium hydroxide. This reaction is typically effected at ambient temperature in the presence of a solvent such as ethanol.
Compounds of formula (IV) where R16 is a halo atom such as iodo may be prepared from compounds of formula (IV) where R16 is hydroxy by reaction with a suitable halogenating agent such as methyltriphenoxyphosphonium iodide. This reaction is typically effected in the presence of a solvent such as N,N-dimethylformamide at ambient temperatures.
Compounds of formula (IV) where R16 is a hydroxy group may be prepared according to the method of Codington, et. al. J. Org. Chem. 1964, 29, 558.
Compounds of formula (III) wherein L1, R1 and R2 are protected hydroxy groups, such as esters, most preferably OC(O)CH3, may be prepared by literature methods well known to a person skilled in the art. For instance, the compound of formula (III) which is in the beta-D-ribofuranosyl configuration may be prepared according to the method of Kiss, J. et al, Helv. Chim. Acta. 1982, 65, 1522.
Compounds of formula (II), wherein R3 is hydrogen or a halo atom, most preferably chloro or bromo, and R4, R5, R6 and R7 are as hereinbefore defined, may be prepared in accordance with the methods described in PCT specifications WO 92/07867 incorporated herein by reference. Alternatively, compounds of formula (II), wherein R3 is hydrogen or a halo atom, most preferably chloro or bromo, and R4, R5, R6 and R7 are as hereinbefore defined, may be prepared in accordance with the methods described by Leroy Townsend, et al. J. Med. Chem., Vol. 38, 1995, pg. 4098.
Alternatively, compounds of formula (II) wherein R3 is xe2x80x94NR8R9, wherein R8 and R9 are as hereinbefore defined, may be prepared by reacting a compound of formula (V) 
wherein R4, R5, R6 and R7 are as hereinbefore defined, with an agent capable of cyclizing the diamine into a benzimidazole. Typically, compounds of formula (V) may be reacted with an isothiocyanate of formula (VI)
Sxe2x95x90Cxe2x95x90NR8xe2x80x83xe2x80x83(VI)
wherein R8 is as hereinbefore defined. The reaction may be carried out in the presence of an agent to promote cyclization such as methyl iodide or a carbodiimide such as dicyclohexyl carbodiimide or 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate in the presence of an aprotic aromatic solvent such as toluene and most preferably pyridine and at an elevated temperature, preferably 75-150xc2x0 C.
Compounds of formula (VI) may be prepared by methods well known to a skilled person or readily available in the chemical literature or obtained commercially.
Compounds of formula (II) wherein R3 is hydrogen may be obtained commercially or alternatively may be prepared by reacting a compound of formula (V) wherein R4, R5, R6 and R7 are as hereinbefore defined with formamidine or most preferably formic acid at ambient temperature to 100xc2x0 C., most preferably 80xc2x0 C.
Compounds of formula (V) may be prepared by methods well known to a skilled person or readily available in the chemical literature or obtained commercially.
Alternatively, compounds of formula (V) may be conveniently prepared from compounds of formula (VII) 
wherein R4, R5, R6 and R7 are as hereinbefore defined, in the presence of a reducing agent, reduced iron for example, and in the presence of an acid, most preferably hydrochloric acid, and in the presence of a solvent such as ethyl alcohol and in the temperature range of 50-78xc2x0 C. (B. Fox and T. L. Threlfall, Org. Syn. Coll. Vol. 5, 1973, p. 346). Alternatively, such ortho phenylenediamines may be prepared in the presence of a reducing agent such as Raney nickel also in the presence of hydrogen. This reaction is also run in the presence of a solvent, ethyl alcohol for example, at ambient temperature (K. Dimroth, et al, Org. Syn. Coll. Vol. 5, 1973, p.1130). Alternatively, such ortho phenylenediamines may be prepared in the presence of a reducing agent such as sodium hydrosulfite. Typically this reaction is effected in the presence of a polar, protic solvent, preferably a mixture of water and ethanol, and at an elevated temperature, preferably reflux.
Compounds of formula (VII) may be prepared by methods well known to a skilled person or are readily available commercially. Alternatively, compounds of formula (VII), where R4 is a halogen atom such as fluorine, chlorine or bromine atom, and R5, R6 and R7 are as hereinbefore defined, may be prepared from compounds of formula (VII) wherein R4 is hydrogen by reaction with an appropriate halogenating agent such as 1 -fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), N-chlorosuccinimide or N-bromosuccinimide, in the presence of an aprotic solvent such as acetonitrile or N,N-dimethylformamide and at an elevated temperature from 50-100xc2x0 C.
Alternatively, compounds of formula (VII) wherein R5 is xe2x80x94SR12 (wherein R12 is as hereinbefore defined) may be prepared from compounds of formula (VII) wherein R5 is a halo atom and R4, R6, R7 and R8 are as hereinbefore defined by reaction with HSR12. This reaction is typically effected in the presence of a strong base such as sodium or potassium hydride and in the presence of a solvent such as dimethylsulfoxide, most preferably N,N-dimethylformamide at ambient temperatures.
Alternatively, compounds of formula (VII) may advantageously be prepared from compounds of formula (VIII), 
wherein R17 is hydrogen, R18 is a protecting group such as an amide, trifluoroacetamide for example, and R4, R5, R6 and R7 are as hereinbefore defined, by reaction with a nitrating agent such as nitric acid. This reaction is effected in a solvent such as sulfuric acid at temperatures of xe2x88x9220 to 25xc2x0 C., most preferably at 0xc2x0 C. The protecting group, R18, may be conveniently removed at the end of the reaction sequence with either acid, 2 normal sulfuric acid for example, or base, sodium carbonate in methanol and water for example, at temperatures of 25-100xc2x0 C.
Compounds of formula (VIII) wherein R17 is hydrogen and R18 is a protecting group such as an amide, trifluoroacetamide for example, and R4, R5, R6 and R7 are as hereinbefore defined, may be prepared from compounds of formula (VIII) wherein R17 and R18 are hydrogen and R4, R5, R6 and R7 are as hereinbefore defined by reaction with an appropriate acylating agent such as trifluoroacetic anhydride. These reactions are effected in the presence of an aprotic solvent such as acetontrile, most preferably 1,4-dioxane, from xe2x88x9210 to 40xc2x0 C., most preferably at 0xc2x0 C.
Alternatively, compounds of formula (VII) in which R4, R5, R6 and R7 are as hereinbefore defined can be prepared from compounds of formula (IX) 
wherein R19 is a halo atom, fluoro or chloro atom for example, by reaction with ammonia. These reactions are typically effected in the presence of a solvent such as ethyl alcohol or 1,4-dioxane and at elevated temperatures, preferably 100xc2x0 C.
Compounds of formula (VIII) in which R17 and R18 are hydrogen and R4, R5, R6 and R7 are as hereinbefore defined may be prepared by methods well known to a skilled person or readily available in the chemical literature or obtained commercially.
Compounds of formula (IX) may be obtained commercially or may be readily prepared by a person skilled in the art.
Compounds of formula (I) in which R1 is a fluorine atom, R2 is a hydroxy or protected hydroxy group and R3, R4, R5, R6 and R7 are as hereinbefore defined may be prepared by reacting compounds of formula (II), wherein R3, R4, R5, R6 and R7 are as hereinbefore defined, with a compound of formula (X), 
in which R20 is hydrogen, R21 is a hydroxy or protected hydroxy group and L1 is as hereinbefore defined. The reaction of compounds of formula (II) with those of formula (X) may be effected using a Lewis acid such as trimethylsilyl trifluoromethanesulfonate, stannic chloride, or boron trifluoride, the former being preferred. The reaction is generally effected in an aprotic solvent and at an elevated temperature, for example, in acetonitrile at 15-30xc2x0 C. or 1,2-dichloroethane at 70-90xc2x0 C.
Compounds of formula (X) in which R20 is hydrogen and R21 and L1 are as hereinbefore defined may be prepared by reaction of compound of formula (X), in which R20 is hydroxy, R21 is a benzyloxy group and L1 is methoxy with a chlorothionoformate, such as phenyl chlorothionoformate followed by reaction of the intermediate thiocarbonate with a reductant, such as tributyltin hydride. This reaction is typically effected in the presence of a radical initiator, AIBN for instance, and in the presence of an aromatic solvent, toluene for instance. The benzyloxy group can then be removed under reductive conditions using a catalyst, such as palladium on carbon, and a reductant, such as hydrogen. This reaction is also effected in the presence of a polar solvent, such as ethanol, and at 25-100xc2x0 C., preferably ambient temperature.
This intermediate can then converted to a compound of formula (X) in which R20 is hydrogen and R21 and L1 are esters, acetyl esters for instance, by reaction with an acid, acetic acid for instance, and an acylating agent, acetic anhydride for instance. This reaction is typically effected in the acylating agent as solvent at 0-100xc2x0 C., preferably 25xc2x0 C.
Compounds of formula (X) in which R20 is hydroxy, R21 is benzyloxy and L1 is methoxy may be prepared from compounds of formula (X) in which R20 is a protected hydroxy group, such as tert-butyldimethylsilyl ether, and R21 is a hydroxy group, by reaction with a benzylating agent, such as benzyl bromide. This reaction is typically effected in a polar solvent, dimethyl formamide for instance, and at 25-110xc2x0 C., preferably 50xc2x0 C.
Compounds of formula (X) in which R20 is a protected hydroxy group, such as a tert-butyldimethylsilyl ether, R21 is a hydroxy group and L1 is methoxy, may be prepared from compounds of formula (X) in which R20 and R21 are hydroxyl and L1 is methoxy, by reaction with a silylating agent, such as tert-butyldimethylsilyl chloride. This reaction is typically effected in a polar, aprotic solvent such as N,N-dimethylformamide in the presence of a base, imidazole for instance, at 25-100xc2x0 C., preferably ambient temperature.
Compounds of formula (X) in which R20 and R21 are hydroxy and L1 is methoxy, may be prepared from compounds of formula (X) wherein R20 and R21 are protected hydroxy groups, such as tert-butyldimethylsilyl ethers, and L1 is methoxy, by reaction with a fluoride source, tetrabutylammonium fluoride for example. This reaction is typically effected in a polar solvent such as acetonitrile at a temperature of 25-100xc2x0 C., preferably ambient temperature.
Compounds of formula (X) in which R20 and R21 are protected hydroxy groups, such as tert-butyldimethylsilyl ethers and L1 is methoxy, may be prepared from compounds of formula (XI) 
in which R22 and R23 are protected hydroxy groups, such as tert-butyldimethylsilyl ethers, by reaction with a fluorinating agent, diethylaminosulfur trifluoride for example. This reaction is typically effected in an aprotic solvent, such as chloroform or toluene, and at an elevated temperature, preferably 75xc2x0 C.
Compounds of formula (XI) in which R22 and R23 are protected hydroxy groups, such as tert-butyldimethylsilyl ethers and L1 is methoxy, may be prepared from compounds of formula (XI) in which R22 and R23 are hydroxy groups and L1 is methoxy by reaction with a silylating agent such as tert-butyldimethylsilyl chloride. This reaction is typically effected in a polar, aprotic solvent, such as N,N-dimethylformamide, and in the presence of a base such as, imidazole at 25-100xc2x0 C., preferably 25xc2x0 C.
Compounds of formula (XI) in which R22 and R23 are hydroxyl and L1 is methoxy may be readily prepared according to literature conditions well-known to a person skilled in the art.
The compounds according to the invention, also referred to herein as the active ingredient, may be administered for therapy by any suitable route including oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, and intravitreal). It will be appreciated that the preferred route will vary with the condition and age of the recipient, the nature of the infection and the chosen active ingredient.
In general a suitable dose for each of the above-mentioned conditions will be in the range of 0.01 to 250 mg per kilogram body weight of the recipient (e.g. a human) per day, preferably in the range of 0.1 to 100 mg per kilogram body weight per day and most preferably in the range 0.5 to 30 mg per kilogram body weight per day and particularly in the range 1.0 to 20 mg per kilogram body weight per day. Unless otherwise indicated, all weights of active ingredient are calculated as the parent compound of formula (I); for salts or esters thereof, the weights would be increased proportionally. The desired dose may be presented as one, two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day. In some cases the desired dose may be given on alternative days. These sub-doses may be administered in unit dosage forms, for example, containing 10 to 1000 mg or 50 to 500 mg, preferably 20 to 500 mg, and most preferably 100 to 400 mg of active ingredient per unit dosage form.
While it is possible for the active ingredient to be administered alone it is preferable to present it as a pharmaceutical formulation. The formulations of the present invention comprise at least one active ingredient, as defined above, together with one or more acceptable carriers thereof and optionally other therapeutic agents. Each carrier must be xe2x80x9cacceptablexe2x80x9d in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
Formulations include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, and intravitreal) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods represent a further feature of the present invention and include the step of bringing into association the active ingredients with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
The present invention further includes a pharmaceutical formulation as hereinbefore defined wherein a compound of formula (I) or a pharmaceutically acceptable derivative thereof and at least one further therapeutic agent are presented separately from one another as a kit of parts.
Compositions suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Such patches suitably contain the active compound 1) in an optionally buffered, aqueous solution or 2) dissolved and/or dispersed in an adhesive or 3) dispersed in a polymer. A suitable concentration of the active compound is about 1% to 25%, preferably about 3% to 15%. As one particular possibility, the active compound may be delivered from the patch by electrotransport or iontophoresis as generally described in Pharmaceutical Research 3 (6), 318 (1986).
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, caplets, cachets or tablets each containing a predetermined amount of the active ingredients; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g. sodium starch glycollate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent. Molded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredients therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredients in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Pharmaceutical formulations suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by admixture of the active combination with the softened or melted carrier(s) followed by chilling and shaping in molds.
Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
Formulations suitable for parenteral administration include aqueous and nonaqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents; and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Preferred unit dosage formulations are those containing a daily dose or daily subdose of the active ingredients, as hereinbefore recited, or an appropriate fraction thereof.
It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include such further agents as sweeteners, thickeners and flavoring agents.
The following examples are intended for illustration only and are not intended to limit the scope of the invention in any way. xe2x80x9cActive ingredientxe2x80x9d denotes a compound of formula (I) or multiples thereof or a physiologically functional derivative of any of the aforementioned compounds.
The appropriate 1,2-phenylenediamine is combined with the appropriate isothiocyanate (1.0-1.25 mmol/mmol of diamine) and anhydrous pyridine (3-5 mL/mmol of diamine). The resulting mixture is heated to 80xc2x0 C. for 30 min, then 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (1.1-1.35 mmol/mmol of diamine) is added as a solid in one portion. The resulting mixture is allowed to stir at 80-90xc2x0 C. for 3-20 h, after which time it is allowed to cool to room temperature. The mixture is then filtered and the solvents removed in vauco. The remaining residue is dissolved in ethyl acetate and is washed with water, saturated, aqueous soudium chloride, dried over magnesium sulfate, filtered and the solvents are removed under reduced pressure. The products can be recrystallized from either 1,4-dioxane or acetonitrile.
The appropriate 2-(alkylamino)1H-benzimidazole was combined with 1,2-dichloroethane (2-3 mL/mmol of benzimidazole) and N,O-bis(trimethylsilyl)acetamide (1-1.25 mmol/mmol of benzimidazole) and the resulting mixture was heated to 80xc2x0 C. for 30 min. Trimethylsilyl trifluoromethanesulfonate (0.5-0.7 mmol/mmol of benzimidazole) was added and the mixture was allowed to stir at 80xc2x0 C. for an additional 15 min, after which time 1,2,3-tri-O-acetyl-5-deoxy-D-ribofuranose (1-1.25 mmol/mmol of benzimidazole) was added as a solid in one portion. The resulting mixture was allowed to stir at 80xc2x0 C. for 2-20 h, after which time it was allowed to cool to room temperature. It was then diluted with 5% aqueous sodium bicarbonate (10 mL/mmol of benzimidazole) and dichloromethane (3-5 mL/mmol of benzimidazole) and the two-phase mixture was stirred at room temperature for 30 min. The organic layer was collected and the aqueous layer was back-extracted with an additional portion of dichloromethane (3-5 mL/mmol of benzimidazole) and the combined organic layers were dried over magnesium sulfate, filtered and the solvents were removed under reduced pressure using a rotary evaporator. The products were further purified by silica gel chromatography.
The appropriate 2-(alkylamino)-1-(2,3-di-O-acetyl-5-deoxy-beta-D-ribofuranosyl)-1H-benzimidazole was dissolved in ethanol (4-5 mL/ mmol of triacetate). Into a separate flask were placed sodium carbonate (1.0-1.3 mmol/mmol of triacetate), water (1-2 mL/mmol of triacetate), and methanol (3 mL/mmol of triacetate). The sodium carbonate suspension was added to the ethanolic solution of the triacetate at room temperature and in one portion. The resulting mixture was allowed to stir at room temperature for 18 h. The mixture was then diluted with ethyl acetate (25 mL/mmol of triacetate). The organic layer was collected and was washed with saturated aqueous brine (100 mL/mmol of triacetate), dried over magnesium sulfate, filtered, and the solvents were removed by rotary evaporation. The products were further purified by silica gel chromatography.
The appropriate 2,3-di-O-acetyl protected nucleoside was dissolved in dioxane (5 mL) and cooled to 0xc2x0 C. in an ice bath. A 4N solution of LiOH was added dropwise and the resulting mixture was stirred for 30 min at 0xc2x0 C. To this mixture was then added pH 7 buffer (until neutral) and brine. This mixture was then extracted with ethyl acetate (5xc3x9750 mL). The organic layer was dried (MgSO4), filtered, concentrated in vacuo to yield the corresponding deprotected nucleoside.
Amine and 2-bromo-5,6-dichloro-1-(5-deoxy-1-beta-D-ribofuranosyl)-1H-benzimidazole were combined with absolute ethanol (5 mL) in a pressure tube and stirred at 80xc2x0 C. until the benzimidazole was consumed. The reaction mixture was concentrated, dissolved in ethyl acetate (25 mL) and washed with saturated NaHCO3 (10 mL), followed by water (10 mL). The ethyl acetate layer was dried with magnesium sulfate (anhyd), filtered, and evaporated. The crude residue was purified on a silica gel column.